Compounds that participate in cooperative binding and uses thereof

A technology of compounds and macrocyclic compounds, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve insurmountable problems

Pending Publication Date: 2020-02-21
REVOLUTION MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The other 90% is currently considered insurmoun...

Method used

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  • Compounds that participate in cooperative binding and uses thereof
  • Compounds that participate in cooperative binding and uses thereof
  • Compounds that participate in cooperative binding and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0527] Example 1. General Fermentation and Isolation Protocol

[0528] Compounds synthesized by bacterial strains can be fermented and isolated using the following general protocol:

[0529] General Fermentation Protocol

[0530] Strains: Bacterial strains such as Streptomyces malaysiensis DSM41697, other producing strains or genetically modified derivatives that produce FKBP ligands (for example: F1, F2, F3 or structurally similar compounds and their analogs) on solid culture Propagate aseptically on a substrate (eg ISP4).

[0531] Working Cell Bank: Use spores or mycelia produced from cultures grown on solid media plates for 3-14 days at 30°C to inoculate liquid cultures (eg: 40ml ATCC172 broth in a 250ml Erlenmeyer flask ). The culture was incubated at 30°C with shaking for 2-3 days. The resulting cell suspension was mixed with sterile 50% glycerol to obtain a mixture with a final concentration of 15-25% glycerol. Aliquots (approximately 1 ml) of the glycerol-mycelium ...

Embodiment 2

[0562] The separation of embodiment 2.F2 and F3

[0563] F1 (target mass 595), F2 (target mass 609) and compound 3 (target mass 623) Streptomyces malaysian fermentation broth (NRRL B-24313; ATCC BAA-13; DSM 41697; JCM 10672; KCTC9934) were produced by centrifugation in 10 L ; NBRC 16446; CGMCC 4.1900; IFO 16448). F1 and F2 are present in clarified fermentation broth and microbial pellets. The target compound in the supernatant was extracted once with EtOAc at a volume ratio (1:1, v / v). The precipitate was extracted 3 times with 1.5 L of EtOAc-MeOH (9:1, v / v), and each extraction was stirred for 1 h-1.5 h with an overhead stirrer. The organic extracts were filtered through celite. The combined filtrates were evaporated at 35°C until dryness, yielding approximately 30 g of crude extract. The residue was then dissolved in 90 mL of DCM-THF (80:20, v / v), and 60 g of silica gel was added thereto and dried under vacuum at 35°C. The dried residue / silica mixture was loaded onto a ...

Embodiment 3

[0568] The separation of embodiment 3.F22

[0569] 10 L of the fermentation broth produced by the recombinant strain S1806 was centrifuged to obtain a pellet and a supernatant. The particles were extracted 3 times with 1.5LEtOAc-MeOH (9:1, v / v). The organic solvents were combined and concentrated in vacuo to obtain 1.8 g of crude extract. 2 mL of heptane-THF (4:1, v / v) was added thereto for dissolution, and then 2 g of Celite was added to obtain a dry mixture after solvent removal on a rotary evaporator at 30°C. The dried residue / celite mixture was loaded onto a 40 g RediSep silica gold cartridge for column chromatography. The compound was fractionated at 20 mL / min eluting with a linear gradient from 100% n-heptane to 40% EtOAc in heptane (v / v) over 25 min, collecting 50 mL of each fraction. F22 (target mass 607) was mainly enriched in fraction 14 identified by LC-MS analysis. Fraction 14 was then dried under vacuum at 30°C to give 17.8 mg of solid material which was furth...

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Abstract

The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity.

Description

Background technique [0001] The vast majority of small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of said proteins. For example, the cholesterol-lowering drugs statins bind to the enzymatic active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may lead some to believe that small molecule modulators can be discovered for most, if not all, proteins given a reasonable amount of time, effort and resources. But in fact, it's not. Current estimates suggest that only about 10% of all human proteins can be targeted by small molecules. The other 90% is currently considered insurmountable or tricky for small molecule drug discovery. Such targets are often referred to as "undruggable". These undruggable targets include a large and largely untapped repertoire of medically important human proteins. Therefore, there i...

Claims

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Application Information

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IPC IPC(8): A61K47/50C07D498/22C07D498/18
CPCC07D498/18C07D498/22C12N9/90A61K31/453C12Y502/01008C07D211/60C07D237/04C07D401/12C12P17/165C07K5/06078
Inventor M.J.穆尔维希尔M.金
Owner REVOLUTION MEDICINES INC
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